In recent years, pharmaceutical compositions rich in omega-3 (“ω-3” or “n-3”) polyunsaturated fatty acids (“PUFAs”) have been developed to treat a variety of clinical indications. PUFA compositions are derived from natural sources, typically fish oils, and comprise one or more various species of omega-3 PUFAs, omega-6 PUFAs, and other minor components, including mono-unsaturated and saturated fatty acids. The PUFAs in these compositions typically exist either as the free fatty acid or in some other acid-derivatized form, such as ester form, particularly ethyl ester form.
Lovaza®, including its generic counterparts, is an FDA-approved pharmaceutical product for the treatment of severe hypertriglyceridemia and includes a PUFA composition comprising the omega-3 PUFA species eicosapentaenoic acid (“EPA”) and docosahexaenoic acid (“DHA”) in the form of ethyl esters in a weight ratio of about 46:38.
Vascepa® is another FDA-approved pharmaceutical product for the same clinical indication and includes a PUFA composition that is >96% pure EPA in the ethyl ester form, with substantially no DHA.
The nutraceutical product, OMAX3, sold as a dietary supplement and promoted in part to lower triglyceride levels, includes a PUFA composition that comprises EPA and DHA in a weight ratio of about 4.1:1, wherein the EPA and DHA are likewise in the ethyl ester form.
Epanova® (omega-3 carboxylic acids) is another FDA-approved product for the treatment of severe hypertriglyceridemia and includes a PUFA composition comprising EPA and DHA as well as the omega-3 PUFA species docosapentaenoic acid (“DPA”), all in substantially free acid form. Pharmacokinetic studies have demonstrated that EPA and DHA from the free fatty acid formulation in Epanova® are rapidly absorbed, and that absorption is less affected by dietary fat restriction compared with the ethyl ester formulation found in other commonly used omega-3 products. This is because, unlike the omega-3 acid ethyl ester formulations, there is no requirement of pancreatic lipase and carboxylester lipase for the digestion and absorption of Epanova®, enzymes that are produced when patients ingest a meal containing fat. Thus, there is an improved bioavailability of Epanova® under low-fat conditions, which offers a therapeutic advantage in patients with hypertriglyceridemia, who are advised to restrict their daily fat intake.
With the increasing availability and prescription of PUFA-based treatments—such as Lovaza®, Vascepa®, OMAX3, and Epanova®—there is a growing need for the formulation of PUFA compositions into capsular dosage forms that exhibit both therapeutic and commercial advantages.
The approved prescription capsular dosage forms of Epanova® contains 1 g of PUFA composition, resulting in a relatively large (25 mm length) capsule. In some patient populations or circumstances, such capsules may be difficult or inconvenient for patients to swallow, for example if administering to children, the elderly or infirm for whom swallowing is difficult (for example because of a previous stroke or other existing medical condition or because of traumatic injury), or such capsules may not be accepted because of personal preference. In such patient populations or circumstances, it would be convenient to have available a dosage form which could be more readily administered, so that the bioavailability advantages described above which are associated with Epanova® can be made available to all patients who might benefit.
Millicapsule formulations of PUFA compositions are known in the art, for example as commercialized as Lotriga™ and Epadel™ in Japan, both of which comprise approximately spherical millicapsules of 4 mm diameter. Both of these products contain PUFA compositions in ethyl ester form.
We have surprisingly found that it is possible to formulate the free fatty acid PUFA composition used in Epanova® into millicapsules and either:                a) Mimic the bioavailability profile of Epanova® by using a relatively thin (as described hereinafter) coating of poly(ethylacrylate-methylmethacrylate) copolymer but with the potential advantages associated with the size of millicapsules described above; or        b) Potentially reduce the dose of omega-3 fatty acids required to achieve certain lipid profile effects by using uncoated millicapsules.For both cases a) and b), surprisingly the millicapsule formulations show potentially greater stability in respect of glyceride formation than the Epanova® 1 g capsule.        